Esters of the androstane series and process for their manufacture



United States Patent The invention relates to the manufacture of3:17-dihydroxy compounds of the androstane and A -androstene serieswhich contain a hydrocarbon residue in position 17 and are esterified in3-position by sulfobenzoic acid, and

of the salts of said semi-esters.

The new compounds obtained by the present process are distinguished bytheir high antiallergic and antianaphylactic action respectively and canbe used in the treatment of allergic disorders, for example asthma andallergic dermatoses. In the form of their salts the new semi-esters givestable aqueous solutions that can be sterilized with heat withoutundergoing decomposition.

The new sulphobenzoic acid esters are obtained when the secondaryhydroxyl group in position 3 of 3:17-dihydroxy compounds of theandrostane and A -androstene series containing a hydrocarbon radical inposition 17 is esterified with a reactive derivative of sulfobenzoicacid, for example with sulfobenzoic acid anhydride or chloride, and theresulting sulfobenzoic acid esters are converted into salts thereof. Thereaction according to the present process is carried out in knownmanner, if desired in the presence of a suitable diluent, such as ahalogenated hydrocarbon, for example methylene chloride, chloroform, orthe like, and in the presence of a basic agent, such as a tertiaryamine, for example pyridine, triethylamine or dimethylaniline.

Salts are obtained, for example, when an aqueous solu- "tion of the3,8:17,8-di-hydroxy-3-sulfobenzoate or of its pyridine salt is reactedwith a hydroxide, carbonate, bicarbonate or halide of an alkali metal oralkaline earth metal, more especially of sodium, potassium, lithium,calcium, barium, strontium, magnesium, or ammonium, or with an amine. Asamines are suitable aliphatic, cycloaliphatic or araliphatic aminescontaining 1 to 8 carbon atoms, as well as heterocyclic amines, forexample mono-, diand tn'ethylamine, mono-, diand trimethylamine, mono-,diand triisopropylamine, ethyldimethyl-arnine, benzyldiethylamine,cyclohexylamine, dibenzylamine, N:N-dibenzylethylenediarnine, bis orthomethoxy N- methyl-ortho-phenylisopropylamine,methoxyphenyl-isopropylamine, piperidine, morpholine, py-rrolidine,piperazinc and lower alkyl derivatives thereof, such asl-methylpiperidine, 4-ethylmorpholine, l-isopropylpyrrolidine, 1:4-dimethylpiperazine, l-n-butylpiperidine, 2-methylpiperidine,1-methyl-2-methylpiperidine and the like; also amines containingwater-soluble or hydrophilic groups such as mono-, diandtriethanolamine, ethyl-diethanolamine, N-butyl-monoethanolamine,Z-amino-l-butanol, 2-amino-2-ethyl 1:3 propanediol,Z-amino-Z-methyl-lpropanol, trihydroxymethyl-aminomethane,phenylmonoethanolamine, para-tertiary amylphenyl-diethanolamine,galactamine, N-methylglucamine, N-methylglucosamine, ephedrine,phenylephedrine, epinephrine, proceine, and 2- (4'-ter-tiary butyl-26-dimethyl-phenyl-methyl) -imidazoline.

In the starting materials, which can be prepared in known manner, thehydrocarbon radical in position 17 is more especially a saturated orunsaturated aliphatic hydrocarbon radical, for example a methyl, ethyl,propyl, isobutyl, vinyl, allyl, methallyl or ethinyl group. Startingmaterials that contain a methallyl or isobutyl radical in 3,060,174Patented Oct. 23,

position 17 are new, and their manufacture is described in the examples.

The following examples illustrate the invention.

Example 1 A solution of 3.04 grams of 17a-methyl-A -androstene-35:17/3-di0l in cc. of pyridine is treated with 2.76 grams ofortho-sulfobenzoic acid anhydride, and the whole is stirred for 30minutes at C. under nitrogen. A further addition of 0.27 gram ofortho-sulfobenzoic acid anhydride is made, and the mixture is heated for30 minutes at 90 C., whereupon 17a-methyl-A -androstene- 36:17B-diol canno longer be detected in the thin-layer chromatogramme. The reactionsolution is cooled and completely evaporated under reduced pressure. Thecrystalline residue is dissolved in 1 500 cc. of water, fil tered,concentrated in vacuo to cc., and allowed to stand overnight. Thecrystalline product thus formed is suctioned ofi, washed with a smallamount of water and dried at 60 C. in vacuo, to yield 2.8 grams of thepyridine salt of -17a-methyl-A-androstene-3B2l7fi-diol-3-orthosulfobenzoate.

By using meta sulfobenzoic acid chloride there is obtained in ananalogous manner the pyridine salt of 170cmethyl-A-androstene-iifi:'17,8-diol-3-meta-sulfobenzoate.

Example 2 A solution of 3.20 grams of 17a-ethyl-androstane-3/3217fl-dio1 in 80 cc. of pyridine is treated with 2.76 grams oforthosulfobenzoic acid anhydride and stirred for 100 minutes at 90 C.under nitrogen, during which the orthosulfobenzoic acid anhydridedissolves practically completely. After 100 minutes17u-ethyl-androstane- 35:17fl-diol can no longer be detected in thethin-layer chromatogramme. The reaotionmixture is cooled, filtered clearand completely evaporated in vacuo. The residue is dissolved in 500 cc.of water with heating on a water bath, and the solution is filtered andconcentrated to 1 50 cc. under reduced pressure, allowed to standovernight. The crystals formed are suctioned off, washed with water anddried, to yield 3.32 grams of the pyridine salt of 170:.-ethyl-androstane-3 8:17fi-diol-3-ortho-sulfobenzoate.

Example 3 A solution of 3.44 grams of 17a-methallyl-A-androstene-3i3z17fl-diol in 40 cc. of pyridine is treated with 2.76grams of ortho-sulfobenzoic acid anhydride and heated with stirring for30 minutes at 90 C. under nitrogen, during which most of theortho-sulfobenzoic acid anhydride passes into solution. After 30 minutesno starting material can be detected in a thin-layer chromato gramme.The reaction solution is cooled, the undissolved ortho-sulfobenzoic acidanhydride is suctioned oil, and the clear, orange-colored filtrate iscompletely evaporate in vacuo. The reddish brown residue is taken up in300 cc. of 0.1 N-sodium bicarbonate solution with heating, and theproduct is salted outwith grams of sodium chloride. The precipitate iskept overnight, suctioned off, Washed with 30 cc. of saturated sodiumchloride solution, and dried in vacuo at 60 to 70 C., to yield 5 gramsof the sodium salt of 17a-metha llyl-A androstene-3/3z17/3-diol-3-ortho-sulfobenzoate.

The starting material used above can be prepared in the followingmanner:

128 grams of magnesium chipping are activated with 6 grams of iodine,cooled, and then covered with 800 cc. of tetrahydrofuran. 40 cc. of amixture of cc. of tetrahydrofuran and 80 cc. of methallyl chloride arethen run in, and when the reaction has set in, the remainder of thismixture is added in the course of 30 minutes. In the course of minutes asolution of 160 grams of A -androsteno1one acetate and 480 cc. ofmethallyl chloride in 2400 cc. of tetrahydroturan is then added dropwiseto the slightly boiling solution. After rinsing with 240 cc. oftetrahydrofuran, another 140 cc. of methallyl chloride are added within20 minutes to achieve complete dissolution of the magnesium. Thereaction mixture is refluxed for 4 hours, cooled, and poured over amixture of 4000 grams of finely ground ice and 1200 cc. of 4N-hydrochloric acid. The whole is extracted with ether, and the etherealextract is successively Washed repeatedly with 2 N-sulfuric acid, dilutebisulfite solution, Water, N- sodium hydroxide solution and water, driedover sodium sulphate and evaporated. The white crystalline residue (179grams) is subjected to fractional crystallization from acetone andyields 131.5 grams of 17a-methallyl-A androstene-3Bzl1fi-diol, meltingat 169170 C. Optical rotation [oc] -='50.l (c.=0.979% in dioxane).

Example 4 A solution of 52.2 grams of 17a-isobutyl-androstane-3fizl7fl-diol in 600 cc. of pyridine is treated with 41.4 grams ofortho-sulfobenzoic acid anhydride, and the mixture is stirred for 60minutes at 90 C. under nitrogen. At first the reaction mixture turnsslightly red-violet and finally orange, and the ortho-sulfobenzoic acidanhydride passes partially into solution. The reaction mixture is thencooled to 20 to 25 C., the undissolved ortho-sulfobenzoic acid anhydrideis suctioned off and rinsed with 200 cc. of pyridine. The filtrate iscompletely evaporated in vacuo at a temperature gradually rising to 80C., to yield 113.5 grams of a brownish orange residue consisting of thepyridine salt of 17a-isobutyl-androstane1:17,8-diol-3-ortho-sulfobenzoate in addition to orthosulfobenzoic acidanhydride and the pyridine salt of orthosulfobenzoic acid. Theevaporation residue is taken up in 2000 cc. of Water and neutralizedwith 21 grams of sodium bicarbonate. The sodium salt of17a-is0bl1tYlandrostane-3B: 17fi-diol-3-ortho-sulfobenzoate crystallizesout partially. 300 grams of sodium chloride are stirred in and themixture is suction-filtered. The separated sodium salt is stirred with25 00 cc. of water, to form a turbid solution from which the sodium saltis again salted out by stirring in 500 grams of sodium chloride. Theprecipitate is suctioned oflf and dried in vacuo at 60 to 70 C. Yield:84.5 grams of the sodium salt of 17u-isobutylandrostane-3B:17/3-diol-3-ortho-sulfobenzoate which is contaminated withsome sodium chloride. To purify the resulting crude sodium salt it isdissolved with heating in 1000 cc. of rectified alcohol, 2.5 grams offilter asbestos are added, and the whole is filtered. The clear filtrateis concentrated in vacuo to about 200 cc., whereupon the sodium saltcrystallizes out gradually. The whole is kept. overnight,suction-filtered, and the product is washed with 40 cc. of cooledrectified spirit and dried in vacuo at 60 to 70 C. Yield: 72.5 grams ofthe pure sodium salt of 17oc-isobutyl-androstane-3fl17fi-diol-3-ortho-sulfobenzoate, melting at 220-223 C. Optical rotation[OQ =+2.5 (c.=2.00% in aqueous alcohol of 25% strength). 7

Elementary analysis (of the product after-dried in100 C. under 0.01 mm.Hg pressure): C H O SNa. Calculated: C, 64.96%;1-1, 7.81%; Na, 4.15%.Found C, 64.6%; H, 8.0%; Na, 4.4%. V

The starting material used above can be prepared thus:

(a) 268.1 grams of l7a-methallyl-A -androstene- 352175-601 are dissolvedin 7000 cc. of rectified spirit, treated with 40 grams of a palladiumblack catalyst of 5% strength, and the mixture is shaken with hydrogenat 20 to 25 C. under slightly superatomospheric pressure. Thehydrogenation is complete after 8 hours. 10 grams of filter asbestos areadded, the catalyst is suctioned off, and the solution is stirred for 10minutes with 10 grams of decolorizing carbon and then filtered until itis clear. The solution is concentrated under a slight vacuum to 2liters, cooled, kept overnight at 0 C., and the crystallisate issuctioned off. The product is thoroughly washed with 150 cc. ofice-cooled rectified spirit and dried in vacuo at 60 to 70 C. Yield:106.4 grams of 17u-iSO- butyl-androstane-3p:175-diol melting at 180182C. Optical rotation [a] =1.0 (c.==l.034% in dioxane Concentration of themother liquors yields further amounts ofl7oc-isobutyl-androstane-3fi:l7/3-diol melting at 168-169 C. Opticalrotation [a] =i0 (c.=1.00% in dioxane).

(b) A solution of 6.8 grams of l7amethallyl-A androstene-3fl:l7,6-diolin cc. of pyridine is treated with 20 cc. of acet-anhydride and themixture is left to itself for 52 hours at 20-25 C. The yellowish brownreaction solution is completely evaporated in vacuo, the residue isdissolved in ether and washed successively with 2 N-hydrochloric acid,water, 2 N-sodium carbonate solution and water, dried, and againevaporated. Yield: 7.3 grams of a white crystalline residue melting at138-139 C. Which, after recrystallization from methanol, melts at140-141" C. Yield: 6.6 grams of l7u-methallyl-A androstene 35:176 dio1-3acetate. Optical rotation [u] "==50.6 (c.-=1.00% in dioxane).

A solution of 3.87 grams of 17u-methallyl-A -androstene-3B:17fi-diol-3acetate in 120 cc. of rectified spirit is mixed successively with 3times 0.5 grams each of a palladium black catalyst of 5% strength andthen at 20-25 C. shaken under a slightly supcratmospheric pressure withhydrogen. The hydrogenation is complete after 35 hours. The catalyst isfiltered off, the clear solution is completely evaporated, and theresidue is recrystallized from methanol. Yield: 2.12 grams of17a-isobuty1 androstene-3B:17B-diol-3-acetate melting at 8081 C. Opticalrotation [ot'];g=7.7 (c.=1.l68% in diox-ane).

A solution of 8.7 grams of 17a-isobutyl-androstane-35:17,!3-diol-3-acetate in 200 cc. of methanol is treated with 10 cc. of10 N-potassium hydroxide solution, and the whole is refluxed for 30minutes, diluted with water, and the precipitate is taken up in ether,washed successively with dilute hydrochloric acid and water, dried oversodium sulphate, and evaporated. The residue is recrystallized fromrectified spirit, to yield 6.3 grams of l7oc-1S0-butyl-androstane-LB:17/i-diol melting at ISO-183 C.

Example 5 When 17a-propyl-androstane-3B:17fi-diol is reacted asdescribed in the preceding examples, the sodium and potassium salts of17a-propyl-androstane-3fl:l7fl-diol-3- orthosulfobenzoate can beprepared.

Example 6 34.86 g. of 17oc-iSOblltYl-EIDdIOSt3I16-3fiI17fl-(ll01 aredissolved in 400 ml. of pure, dry pyridine. 25.0 g. of metasulfobenzoylchloride are added and the mixture stirred in an atmosphere of nitrogenat an internal temperature of 20-40 C. for 3040 hours until in achromatoplate (system dioxane: water 9:1; indicator 50% sulfuric acid)17a-isobutyl-androstane-3fi: l7fl-diol can no longer be detected. Thereaction solution is then evaporated completely under reduced pressure,the bath temperature being raised gradually. The dark-colored residue isdissolved in 1000 ml. of water, neutralized with 10 g. of sodiumbicarbonate, and 250 g. of sodium chloride are added while stirring,whereupon the sodium salt of isobutyl androstane 3fiz17fl diol 3 metasulfobenzoate precipitates. The mother liquor is separated and thesodium salt taken up in 2000 ml. of water. A turbid solution is obtainedfrom which the sodium salt of 17a isobutyl androstane 3,82175 diol 3metasulfobenzoate is salted out again by stirring in 400 g. of sodiumchloride. The precipitate is filtered off with suction and dried underreduced pressure. The yield is 42.1 g. of the sodium salt of17a-isobutyl-androstane-B13:17,9- diol-3-meta-sulfobenzoate.

What is claimed is:

1. A compound selected from the group consisting of a3-mono-sulfobenzoic acid ester of a compound selected from the groupconsisting of 3,8:17fi-dihydr0xy-androstanes and A -androstenes whichcontain in 17d-POSltiOn a lower aliphatic hydrocarbon residue.

2. An alkali metal salt of a 3-mon0-sulfobenzoic acid ester claimed inclaim 1.

3. An alkaline earth metal salt of a 3-mono-sulfobenzoic acid esterclaimed in claim 1.

4. An amine salt of a 3-mono-sulfobenzoic ester claimed in claim 1derived from an amine selected from the group consisting of analiphatic, a cycloaliphatic, an araliphatic and a heterocyclic aminehaving from 1 to 8 carbon atoms.

'5. The pyridine salt of 17a-methyl-A -androstene- 318:17,8-diol-3-ortho-sulfobenzoate.

6. The pyridine salt of 17u-methyl-A -androstem-3,8: 173-diol-3-meta-su1fobenzoate.

-7. The pyridine salt of 17u-ethyl-androstane-3 S:17B-diol-3-0rtho-sulfobenzoate.

8. The sodium salt of 17a-propyl-androstane-3B:17B-dio1-3-ortho-sulfobenzoate.

9. The potassium salt of 17oc-propyl-androstane-3fi:17B-diol-3-ortho-sulfobenzoate.

.10. The sodium salt of l7tx-methallyl-M-androstene- 3 18:17fl-diol-3-ortho-sulfobenzoate.

12. The sodium salt of 17a-isobutyl-androstane-3 6-17fl-diol-3-ortho-sulfobenzoate.

13. The sodium salt of 17a-isobutyl-androstane-3B:17fl-diol-3-metasulfobenzoate.

14. 3,9:l7p-dihydroxy-androstane having an isobutyl group inNix-position.

15. 3,8:17fl-dihydroxy-A androstene having a methallyl group in17a-position.

16. 17 fl-dihydroxy-A androstene having an isobutyl group in17oc-pOSiti0l1.

Schwenk et a1. Dec. 26, 1939 Tindall July 29, 1958

1. A COMPOUND SELECTED FROM THE GROUP CONSISTING OF A3-MONO-SULFOBENZOIC ACID ESTER OF A COMPOUND SELECTED FROM THE GROUPCONSISITNG OF 3B:17B-DIHYDROXY-ANDROSTANES AND >5-ANDOSTENES WHICHCONTAINS IN 17A-POSITION A LOWER ALIPHATIC HYDROCARBON RESIDUE.